Adrenocortical dysfunction in obesity and the metabolic syndrome.

Recently, it has become evident that the adrenals play a key role in obesity as well as in the metabolic syndrome and their complications. On the one hand, adrenal steroids are involved in physiological regulation of adipose tissue and energy homeostasis and in the pathogenesis of cardiometabolic complications. On the other hand, fat cell-derived factors, adipocytokines, and lipids released from adipose tissue are involved in the modulation of adrenal steroidogenesis. Aldosterone plasma levels are elevated in obesity and in patients with the metabolic syndrome. Recent research has provided evidence that adipocytes secrete factors that stimulate adrenal mineralocorticoid release and sensitize the adrenal cortex to angiotensin II.     

New powers of brown fat: fighting the metabolic syndrome

An understanding of the full powers of brown adipose tissue (BAT) is only successively being accumulated. In a paper in Nature Medicine, Bartelt et al. (2011) add further impressive aspects to the potential powers of BAT in the combat against the metabolic syndrome by demonstrating its vast capacity for triglyceride clearance and glucose disposal.     

Post-traumatic Stress Disorder in children and adolescents: from Sigmund Freud's "trauma" to psychopathology and the (Dys)metabolic syndrome.

Post-traumatic Stress Disorder (PTSD) is an anxiety syndrome that develops after exposure to traumatic life events. Symptoms include re-experience of the initial trauma, avoidance of stimuli associated with the trauma and symptoms of excessive arousal. Neuroendocrine studies in adults with PTSD have demonstrated that basal cerebrospinal fluid (CSF) CRH levels are elevated and urinary cortisol levels are variable--low in the majority of cases--whereas other studies demonstrate no differences in urinary and plasma cortisol concentrations. Urinary catecholamine excretion is higher in PTSD patients than those of control subjects and other psychiatric disorders. Children may differ from adults in their psychologic and physiologic responses to severe stressors. Also, exposure to stress during critical periods of development may have irreversible effects on behavioral maturation and may affect specific vulnerable brain areas, altering CNS development. Similar to findings in adult studies, PTSD in children is characterized by increased sympathetic nervous system (SNS) activity, as indicated by elevated norepinephrine levels in the periphery. High cortisol levels in urine or saliva have been reported in most studies of childhood PTSD, while prospective longitudinal studies concerning the natural history of neuroendocrine changes in pediatric PTSD after an acute stressor are limited. The identification of neurobiologic changes in response to early adverse experiences is of major importance for the prognosis, prevention, management, and treatment of children and adolescents at risk for or suffering from PTSD.     

Effect of the Japanese diet during pregnancy and lactation or post-weaning on the risk of metabolic syndrome in offspring

We examined the effects on offspring of ingestion of the 1975 Japanese diet during pregnancy and lactation and after weaning in mice. Pregnant dams were divided into groups that were fed the Japanese diet or a control diet and raised until offspring were weaned. The offspring after weaning were further divided into groups that were raised on the Japanese diet or the control diet. Ingestion of the Japanese diet after weaning suppressed accumulation of visceral fat in offspring, and reduced the amount of lipids in serum and liver. This effect was weakened if the Japanese diet was only ingested during pregnancy and lactation. Therefore, it was suggested that ingestion of the Japanese diet of mothers during pregnancy and lactation weakens the lipid accumulation inhibitory effect of the Japanese diet in children.     

Hypothalamic lipotoxicity and the metabolic syndrome

Ectopic accumulation of lipids in peripheral tissues, such as pancreatic β cells, liver, heart and skeletal muscle, leads to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. Current evidence has demonstrated that hypothalamic sensing of circulating lipids and modulation of hypothalamic endogenous fatty acid and lipid metabolism are two bona fide mechanisms modulating energy homeostasis at the whole body level. Key enzymes, such as AMP-activated protein kinase (AMPK) and fatty acid synthase (FAS), as well as intermediate metabolites, such as malonyl-CoA and long-chain fatty acids-CoA (LCFAs-CoA), play a major role in this neuronal network, integrating peripheral signals with classical neuropeptide-based mechanisms. However, one key question to be addressed is whether impairment of lipid metabolism and accumulation of specific lipid species in the hypothalamus, leading to lipotoxicity, have deleterious effects on hypothalamic neurons. In this review, we summarize what is known about hypothalamic lipid metabolism with focus on the events associated to lipotoxicity, such as endoplasmic reticulum (ER) stress in the hypothalamus. A better understanding of these molecular mechanisms will help to identify new drug targets for the treatment of obesity and metabolic syndrome.     

Endothelial lipase and the metabolic syndrome

PURPOSE OF REVIEW: Several in-vitro and in-vivo animal studies indicate that endothelial lipase plays a key role in the intravascular remodeling of lipoproteins, particularly HDL. This review integrates this body of knowledge with more recent data in humans linking endothelial lipase to HDL metabolism and other features of the metabolic syndrome. RECENT FINDINGS: Human studies generally support the involvement of endothelial lipase in modulating plasma HDL. The association between endothelial lipase and metabolism of apolipoprotein B-containing lipoproteins in humans, however, has not been entirely consistent with previous findings in vitro and in animals. Finally, elevated plasma endothelial lipase has been associated with abdominal obesity and hypertension, and there is now compelling evidence that inflammation and in-vivo regulation of endothelial lipase may be intrinsically related. SUMMARY: Accumulating evidence indicates that endothelial lipase plays a role in the etiology of the atherogenic plasma lipoprotein profile characteristic of the metabolic syndrome. Increased endothelial lipase activity is linked to the underlying proinflammatory state in this condition. Further studies are required, however, to define the extent to which endothelial lipase contributes to the dyslipidemia of the metabolic syndrome relative to other important regulating factors, such as lipoprotein lipase, hepatic lipase, and cholesterol ester transfer protein.     

Leptin and metabolic syndrome

Obesity is characterized by increased concentration of leptin and disturbance of the feedback between hyperleptinaemia and enhanced appetite. The hyperleptinaemia is often combined with hyperglycaemia and arterial hypertension and seems to be a predictor of acute cardiovascular events. Leptin inhibitors might be used in the future for therapy in case of the metabolic syndrome.     

"The metabolic syndrome... is dead": These reports are an exaggeration

The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol--presumably low density lipoprotein-cholesterol (LDL-C)--levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful "life-style changes" approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery.     

Muscle lipid metabolism in the metabolic syndrome

PURPOSE OF REVIEW: The metabolic syndrome has been emphasized as affecting an important subset of individuals at high risk for cardiovascular disease leading the National Cholesterol Educational Program Adult Treatment Panel III in highlighting awareness of insulin-resistance syndrome. Insulin resistance is thought to be an underlying feature of the metabolic syndrome and in the last few years efforts have been performed to assess the effects of ectopic fat accumulation on whole-body glucose metabolism and on the pathogenesis of insulin resistance. RECENT FINDINGS: Abnormality of fatty acid metabolism and ectopic fat accumulation within skeletal muscle has been measured using the traditional biopsy technique but this field of investigation has been exploited considerably more recently thanks to the use of non-invasive H-magnetic resonance spectroscopy. Initial data supported the hypothesis that a strong causal relationship between increased intra-myocellular lipid (IMCL) content and whole-body insulin resistance might exist. Indeed, experimental evidence is still controversial especially when the modulation of the IMCL content is induced by physical exercise and nutritional interventions. SUMMARY: It has been suggested recently that the flux of muscular fatty acids as a source of oxidative energy may play a pivotal role into the development of the abnormalities of muscle and whole-body energy metabolism, potentially as the basis of the pathogenesis of obesity, the metabolic syndrome and type 2 diabetes.     

The metabolic syndrome and adipocytokines

Visceral fat accumulation has been shown to play crucial roles in the development of cardiovascular disease as well as the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension and the so-called metabolic syndrome. Given these clinical findings, adipocytes functions have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that have been termed adipocytokines, which secrete various bioactive substances. Among adipocytokines, tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and may contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. On the contrary to these adipocytokines, adiponectin, an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, especially focusing on adiponectin is discussed with respect to cardiovascular diseases.     

肠道稳态与代谢综合征

代谢综合征(metabolic syndrome,MS)是具有多样临床表现的物质代谢紊乱,包括肥胖和胰岛素抵抗等。它能增加糖尿病和心血管的发病率。目前它的病因尚不明确,与环境、免疫、遗传等因素有关。研究表明代谢综合征患者肠道菌群结构较正常人有所改变,肠道稳态被打破。宿主共生菌在正常生理条件下,参与到宿主的物质代谢、营养吸收、免疫反应等过程中,同时其也受宿主基因、营养情况和生活方式的影响。不断深入了解宿主和肠道菌群之间的作用关系,能有效提出具有针对性的治疗代谢综合征的个性化防治策略。     

Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome

The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease (CKD) in Japanese individuals with metabolic syndrome. The study population comprised 2150 Japanese individuals with metabolic syndrome, including 411 subjects with CKD [estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m²] and 1739 controls (eGFR ≥ 60 mL/min/1.73m²). The genotypes for 100 polymorphisms of 80 candidate genes were determined. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that nine polymorphisms of APOE, ABCA1, PTGS1, TNF, CPB2, AGTR1, OR13G1, and GNB3 were associated (P < 0.05) with the prevalence of CKD. Among these polymorphisms, the ? 219G → T polymorphism of APOE (rs405509) was most significantly associated with CKD in Japanese individuals with metabolic syndrome.     

Mast cells and metabolic syndrome

Mast cells are critical effectors in the development of allergic diseases and in many immunoglobulin E-mediated immune responses. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell-specific chymase and tryptase. Like macrophages and T lymphocytes, mast cells are inflammatory cells, and they participate in the pathogenesis of inflammatory diseases such as cardiovascular complications and metabolic disorders. Recent observations suggested that mast cells are involved in insulin resistance and type 2 diabetes. Data from animal models proved the direct participation of mast cells in diet-induced obesity and diabetes. Although the mechanisms by which mast cells participate in these metabolic diseases are not fully understood, established mast cell pathobiology in cardiovascular diseases and effective mast cell inhibitor medications used in pre-formed obesity and diabetes in experimental models offer hope to patients with these common chronic inflammatory diseases. This article is part of a Special Issue entitled: Mast cells in inflammation.     

代谢综合征与下丘脑功能改变

下丘脑对瘦素/胰岛素敏感性降低导致的能量平衡调节异常和下丘脑-垂体-肾上腺轴功能紊乱参与了代谢综合征的发生发展,下丘脑功能改变是代谢综合征重要的中枢病理生理学机制。代谢综合征下丘脑功能改变与局部炎性细胞因子表达增加有关,IKK/NF-κB激活可能是下丘脑功能改变的关键分子机制。